Is DSC2 p.Gln331His (c.993G>C) pathogenic?

DSC2 p.Gln331His (c.993G>C) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.7529); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with DSC2 p.Gln331His (c.993G>C)?

DSC2 p.Gln331His (c.993G>C) is associated with cardiomyopathy, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Gln331His (c.993G>C) in the general population?

DSC2 p.Gln331His (c.993G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSC2 p.Gln331His (c.993G>C)?

AlphaMissense predicts likely pathogenic (score 0.7529) — an in-silico prediction, not a clinical call.

DSC2 p.Gln331His

c.993G>C · VCV3386539

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7529 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,378)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.7529	likely pathogenic
REVEL	0.279	benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Constraint at this position
Conservation	phyloP -5.4	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	10.23	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,378). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DSC2
Protein: p.Gln331His
Coding: c.993G>C
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31083010 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 331: the cadherin 2 domain

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Gln331Ter Pathogenic ★ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 c.942+6A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala13Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dsc2-p-gln331his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown